Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4
Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4
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DOI：
10.1152/ajpregu.00793.2005
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发表时间：
2006-10-01
影响因子：
2.8
通讯作者：
Billiar, Timothy R.
中科院分区：
文献类型：
--
作者：
Levy, Ryan M.;Prince, Jose M.;Billiar, Timothy R.
广泛的软组织损伤和骨折是多重损伤患者初始全身炎症反应的重要因素。全身炎症可导致远离创伤部位的器官功能障碍。识别外周损伤和随后激活免疫反应的机制尚不清楚。toll样受体（TLRs）可以识别微生物产物，但也可以识别受损组织释放的危险信号。在这里，我们报告外周组织创伤引发全身炎症和远端器官功能障碍。此外，这种对无菌局部损伤的全身反应需要toll样受体4 （TLR4）。与野生型（C3H/HeOuJ）小鼠相比，TLR4突变型（C3H/HeJ）小鼠对双侧股骨骨折的全身和肝脏炎症反应降低。肝脏创伤诱导的核因子(NF)- κ B激活需要功能性TLR4信号。CD14（-/-）小鼠未能显示出对骨折诱导的全身炎症和肝细胞损伤的保护作用。因此，我们的研究结果也反对肠道来源的LPS对这一过程的贡献。这些发现确定了TLR4在严重创伤损伤的快速识别和反应途径中的关键作用。这些发现在进化背景下的应用表明，多细胞生物已经进化到使用相同的模式识别受体来生存创伤和感染挑战。
Extensive soft tissue injury and bone fracture are significant contributors to the initial systemic inflammatory response in multiply injured patients. Systemic inflammation can lead to organ dysfunction remote from the site of traumatic injury. The mechanisms underlying the recognition of peripheral injury and the subsequent activation of the immune response are unknown. Toll-like receptors (TLRs) recognize microbial products but also may recognize danger signals released from damaged tissues. Here we report that peripheral tissue trauma initiates systemic inflammation and remote organ dysfunction. Moreover, this systemic response to a sterile local injury requires toll-like receptor 4 (TLR4). Compared with wild-type (C3H/HeOuJ) mice, TLR4 mutant (C3H/HeJ) mice demonstrated reduced systemic and hepatic inflammatory responses to bilateral femur fracture. Trauma-induced nuclear factor (NF)-kappa B activation in the liver required functional TLR4 signaling. CD14(-/-) mice failed to demonstrate protection from fracture-induced systemic inflammation and hepatocellular injury. Therefore, our results also argue against a contribution of intestine-derived LPS to this process. These findings identify a critical role for TLR4 in the rapid recognition and response pathway to severe traumatic injury. Application of these findings in an evolutionary context suggests that multicellular organisms have evolved to use the same pattern recognition receptor for surviving traumatic and infectious challenges.